Lacrimal system drug delivery device

ABSTRACT

This invention is in the field of medical intervention related to the lacrimal system. The invention relates to a lacrimal system device and methods of using the device for drug delivery to the eye, sinuses and/or periocular tissues.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a continuation of, and claims priority to,U.S. National Phase application Ser. No. 14/760,307 filed under 35U.S.C. § 371, on Jul. 10, 2015, to be issued as U.S. Pat. No. 10,993,834on May 4, 2021, claiming priority to PCT International Application No.PCT/US2014/011477, filed on Jan. 14, 2014, which claims priority under35 U.S.C. § 119 to U.S. Provisional Application No. 61/752,742, filed onJan. 15, 2013. These applications are incorporated herein by referencein their entireties for all purposes.

FIELD

This invention is in the field of medical intervention related to thelacrimal system. The invention relates to a lacrimal system device andmethods of using the device for drug delivery to the eye, sinuses and/orperiocular tissues.

BACKGROUND

A variety of challenges face patients and physicians in the area ofocular and respiration disease or disorder management, includingadequate drug delivery to the eyes or nasal passage and treatment of dryeyes. In ocular management, for example, many current ocular drugdelivery systems require repetitive manual drug administration and areoften ineffective due to a lack of patient compliance or inadequate drugconcentrations reaching the eye. Many current tear flow blockagetechniques also have drawbacks, including being irreversible in nature.

A previously used approach of drug delivery to an eye or perioculartissues can be to place a removable, drug-releasing punctal implant intoa punctum. It is believed that by allowing for the sustained release ofone or more drugs, the present punctal implants can overcome some of thedrawbacks associated with current drug administration (i.e., manual dropinstillation), such as poor patient compliance, waste, untimelyapplication, or non-localized delivery. One approach to blocking of tearflow from the eye is to place a removable, but retainable, punctalimplant into the punctum, commonly called punctal plugs. Such punctalplugs have been suggested to provide an avenue for extended release drugdelivery, however they suffer from several drawbacks including:dislodgement and displacement (especially if a patient rubs the eye orlid too vigorously or sneezes), limited medication reservoir capacity,and uneven delivery of therapeutic agents in patients with poor tearproduction as agent dispersal is dependent upon distribution viadilution in available tears on the tear film of the eye. What is neededis a device that can supply long term, steady release of therapeuticagents to treat subjects in need of delivering active agents to the eyeand/or periocular tissues.

SUMMARY

This invention is in the field of medical intervention related to thelacrimal system. The invention relates to a lacrimal system device andmethods of using the device for drug delivery to the eye, sinuses and/orperiocular tissues.

In one embodiment, the invention relates to a lacrimal system drugdelivery device, comprising: a) a reservoir having a loading port and anexit port wherein said reservoir has elastic properties, b) a first tubeconnected to said exit port, and c) a second tube comprising a flowlimiting port connected to said first tube. In one embodiment, saidreservoir has self-compression properties. In another embodiment, saidfirst tube and second tube comprise one continuous tube. In oneembodiment, said first and second tubes are one continuous tube thatcontains a flow limiting port on the distal end of said device. Inanother embodiment, said device comprises a second set of a first tubeconnected to said exit port, and a second tube comprising a flowlimiting port connected to said first tube. In one embodiment, saiddevice further comprises a third tube connected to said loading port.FIG. 3A shows the inflated device by itself. FIG. 3B shows the majorparts of the lacrimal system with which the device interacts. FIG. 3Cshows an embodiment of the device, where there are two sets of tubesextending through each lacrimal duct to each punctum (superior punctumand an inferior punctum, upper punctum and a lower punctum,respectively). The device may have one or two sets of tubes. FIG. 3Dshow an embodiment of the device with two sets of tubes, but without thethird flushing/refilling tube. FIG. 3E shows a preferred embodiment, adevice with a single set of tubes terminating in a flow limiting port 5,said port terminates in the upper (superior) punctum. FIG. 3F shows thedevice with a single set of tubes terminating in a flow limiting port 5,said port terminates in the lower (inferior) punctum. In one embodiment,said device further comprises an internal spring connected to aninternal plunger connected to said exit port. In one embodiment, saidinternal plunger enables the constant release of said compositionwithout relying on said elastic reservoir. In one embodiment, nitinolwire (or other material) springs are used internal to the lacrimalportion of the device that pulls an internal plunger towards the distalopening as fluid is released to allow for constant fluid deliverywithout relying on a constant pressure elastomeric balloon. In oneembodiment, said device further comprises a microelectromechanicalsystems (MEMS) spring pressure regulator. In one embodiment, saidelastic reservoir further comprises a fluid comprising a compositionwith an active ingredient. In one embodiment, said elastic reservoirenables anatomical fixation. In one embodiment, said anatomical fixationis a device retention feature, much like a foley catheter retentionfeature. In one embodiment, said exit port is connected to an internalplunger. In one embodiment, said exit port is connected to internalsprings connected to said internal plunger. In one embodiment, saiddevice further comprise a microelectromechanical systems spring pressureregulator. In one embodiment, said device is made of bioerodiblematerials. In one embodiment, said device is made of medical gradematerials. In one embodiment, said flow limiting port comprises a hole.In one embodiment, said flow limiting port comprises a filter. In oneembodiment, said flow limiting port comprises at least one ePTFEmembrane. In one embodiment, said ePTFE membranes may be used toregulate flow out of the distal end of said device. For example, ePTFEwith 0.0003″+/−0.0001″ (0.00762 mm+/−0.00254 mm) thickness and with aporosity of 80%+/−10% and a mean flow pore size of 0.2 to 0.5 micron. Inone embodiment, one or more layers of ePTFE material can be used forflow regulation. In one embodiment, the flow of said fluid out of saiddevice is gravity dependent. In one embodiment, the flow of said fluidout of said device is limited by a gravity dependent valve. In oneembodiment, the flow of said fluid out of said device is controlled by acut-off valve that is accessible by an operator (patient or physician)to decrease flow at given times of the day when treatment might not beneeded (while sleeping for example). In one embodiment, the elasticreservoir will deliver fluid+/−active ingredients to the ocular surfaceat a fixed rate between 0.1 microliters and 30.0 microliters per day fora minimum of one week. In another embodiment, the delivery is achievedfor a minimum of 60 days.

In another embodiment, the invention relates to a method of treatment,comprising: a) providing: i) a subject comprising lacrimal ducts and alacrimal sac, ii) a lacrimal system drug delivery device, comprising: A)a elastic reservoir comprising a composition with at least one activeingredient, wherein said reservoir is capable of insertion inside saidlacrimal sac, B) a first tube with a lumen extending from said elasticreservoir through either the upper or lower of the lacrimal ducts fromwithin the naso-lacrimal duct, and C) a second tube with a flow limitingport connected to said first tube, wherein said second tube terminateswith said flow limiting port in a punctum in contact with the tear filmof the eye, b) inserting said drug delivery device into said lacrimalsystem; and c) administering said composition to said subject using saidlacrimal system drug delivery device. In one embodiment, said reservoirhas self-compression properties. In another embodiment, said first tubeand second tube comprise one continuous tube. In another embodiment,said device comprises a second set of a first tube connected to saidexit port and a second tube comprising a flow limiting port connected tosaid first tube wherein said second set second tube terminates with saidflow limiting port in the other punctum in contact with the tear film ofthe eye. In one embodiment, said device further comprises a third tubeconnected to said elastic reservoir, wherein said third tube extendsfrom said elastic reservoir into the nasolacrimal duct wherein itterminates. In one embodiment, said third tube that extends through thelarcrimal duct and up to the nasal opening of the duct. In oneembodiment, said device further comprises a cut-off valve. In oneembodiment, said device comprises bioerodible materials. In oneembodiment, said device comprises internal composition columns with saidbioerodible materials. In one embodiment, the erosion of saidbioerodible materials open up inlet pores sequentially allowing alongsaid internal composition column which would enable for pulsed dosing ofsaid composition. In one embodiment, said active ingredient consists ofartificial tears, glaucoma drops, anti-inflammatory agents, nonsteroidalagents, antibiotics, biologics, proteins, aptamers, nucleic acids,cytokines, plasma, sympahtomemetics, parasympathomemetics, prostaglandinanalogues, beta blockers, alpha-agonists, anti-VEGF agents and otheragents known to treat diseases of the eye or periocular tissues. In oneembodiment, said elastic reservoir may be accessed through said thirdtube for the process of flushing and refilling. In one embodiment, theflow of said fluid out of said device is controlled by a cut-off valvethat is accessible by an operator to decrease flow at given times whentreatment is not desired. In one embodiment, said flow limiting portregulates the flow of said composition from said device. In oneembodiment, said flow limiting port comprises at least one ePTFEmembrane. For example, ePTFE with 0.0003″+/−0.0001″ (0.00762mm+/−0.00254 mm) thickness and with a porosity of 80%+/−10% and a meanflow pore size of 0.2 to 0.5 micron._In one embodiment, said flowlimiting port comprises at least one layer of ePTFE material. In oneembodiment, nano to micron size holes at the tip of the device are usedto control egress of fluid rather than ePTFE material. In oneembodiment, the elastic reservoir will deliver fluid+/−activeingredients to the ocular surface at a fixed rate between 0.1microliters and 30.0 microliters per day for a minimum of one week. Inanother embodiment, the delivery is achieved for a minimum of 60 days.

In one embodiment, the invention relates to a lacrimal system drugdelivery device, comprising: a) an reservoir having a loading port andan exit port, b) a first tube connected to said exit port, and c) asecond tube comprising a flow limiting port connected to said firsttube. In one embodiment, said first and second tubes comprise onecontinuous tube. In one embodiment, said reservoir has self-compressionproperties. In one embodiment, said loading and exit port are the sameport. In one embodiment, said reservoir comprises a nanoporous material.In one embodiment, said reservoir comprises a microrous material. In oneembodiment, the balloon component 1 of the device may be designed onlyfor fixation and not delivery (like foley catheter retention feature).In one embodiment, nitinol wire (or other material) springs 10 are usedinternal to the lacrimal portion of the device that pulls an internalplunger 8 towards the distal opening as fluid is released to allow forconstant fluid delivery without relying on a constant pressureelastomeric balloon 1. In one embodiment, the device comprisesbioerodible or biodegradable materials 6. In one embodiment, saidbioerodible 6 or biodegradable materials 6 open up inlet poressequentially allowing along the internal fluid column which would enablefor pulsed dosing. In one embodiment, the device further comprises amicroelectromechanical systems (MEMS) spring pressure regulator 12. Inone embodiment, ePTFE membranes 7 may be used to regulate flow out ofthe distal end of said device. For example, ePTFE with 0.0003″+/−0.0001″(0.00762 mm+/−0.00254 mm) thickness and with a porosity of 80%+/−10% anda mean flow pore size of 0.2 to 0.5 micron. In one embodiment, one ormore layers of ePTFE material can be used for flow regulation. FIG. 5shows an angled view of the device. FIG. 6 shows an angled view of thedevice. FIG. 7 shows a tube distal end close-up. FIGS. 8A & B show oneembodiment of the device. FIG. 8A shows the device consisting of amicroporous balloon 1 that can deliver drug directly to tissue spacessuch as sinuses. In contains a tube (3, 2) with a flow limitingport/exit port 5 which may or may not contain a distal membrane 7 whichcan serve as a simple filling port 7 (located in the punctum or in theconjunctiva/caruncle or surrounding tissues) to refill the microporousballoon 1 as needed. The balloon 1 then oozes out medication/fluid totargeted tissues. FIG. 8B shows that a nitinol cage 13 or otherstructural features may serve to exert pressure on the microporousballoon/reservoir 1. Instead of drug/composition being delivered onlythrough the distal part 7, this option gives us the capability todeliver drug directly from the reservoir 1 to surrounding tissues withor without delivery through the distal part as well. There are certaindiseases that would benefit from this approach, like chronic sinusitis.FIG. 9 shows a device where there is a microporous balloon/elasticreservoir 1 and a distal membrane 7 where the first tube 2 contains bioerodible elements 6, and an internal plunger 8, and an exit port 9 isconnected to internal springs 10 connected to said internal plunger 8,microelectromechanical systems spring pressure regulator 12, andbioerodible materials 6 open up inlet pores sequentially allowing alongsaid internal composition column which would enable for pulsed dosing ofthe active agent composition. FIG. 10 shows one embodiment of the devicewhere a separate nitinol device 13 is constructed to surround thereservoir 1 prior to filling so that the nitinol cage 13 containsstraight wires. Once filled, the reservoir 1 pushes the nitinol out andthe nitinol then acts on the non-elastic or semi-elastic material toslowly push fluid out towards the flow limiting membrane 7 at the top(exit port). In one embodiment the device comprises a reservoir and afirst tube. In one embodiment, the device comprises a nonelasticreservoir that is contained within surrounding material that allows forcompression of said reservoir. In one embodiment, a nitinol wire, springor cage may be used to provide the compression of said reservoir. In oneembodiment, the reservoir is substantially nonelastic. In oneembodiment, said reservoir is made from a microporous or nanoporousmaterial. In one embodiment, the composition within said reservoir isreleased through the pores of the reservoir material. In someembodiments, the device comprises a protective sleeve be placed oversaid reservoir. In one embodiment, said sleeve protects against leaksentering the nasal duct or other tissue compartments. In one embodiment,said device contains fluorescent material or coloring to allow fordetection and position confirmation by the user (physician or patient).In one embodiment, said reservoir is implanted within the sinusessurrounding the eye. In one embodiment, the punctal portion or distalend allows for filling the elastic reservoir with medication, but theelastic reservoir sits in a sinus and allows for delivery of drugthrough a microporous balloon. In one embodiment, the punctal portion isimplanted through the caruncle or through the conjunctiva (similar toimplantation of a jones tube) and allow for the microporous balloon pumpto deliver drug directly to the sinus or other tissue areas surroundingthe eye. In another embodiment, the device delivers medication through amicroporous reservoir in addition to the primary embodiment thatdelivers to a tube with a hole positioned at the punctum. In oneembodiment, the compressed reservoir will deliver fluid+/−activeingredients to the ocular surface at a fixed rate between 0.1microliters and 30.0 microliters per day for a minimum of one week. Inanother embodiment, the delivery is achieved for a minimum of 60 days.

In another embodiment, the invention relates to a method of treatment,comprising: a) providing: i) a subject comprising lacrimal ducts, ii) alacrimal system drug delivery device, comprising: A) a reservoircomprising a composition with at least one active ingredient, whereinsaid reservoir is capable of insertion inside said tissues surroundingthe eye, including, but not limited to the lacrimal sac, sinuses, andpunctual area, B) a first tube with a lumen extending from saidreservoir through either the upper or lower of the lacrimal ducts fromwithin the naso-lacrimal duct, and C) a second tube, connected to saidfirst tube, with a flow limiting port connected to said first tube,wherein said second tube terminates with said flow limiting port in apunctum in contact with the tear film of the eye, b) inserting said drugdelivery device into said lacrimal system; and c) administering saidcomposition to said subject using said lacrimal system drug deliverydevice. In one embodiment, said reservoir has self-compressionproperties. In one embodiment the device comprises a reservoir and afirst tube. In one embodiment, the device comprises a nonelasticreservoir that is contained within surrounding material that allows forcompression of said reservoir. In one embodiment, a nitinol wire, springor cage may be used to provide the compression of said reservoir. In oneembodiment, the reservoir is substantially nonelastic. In oneembodiment, said reservoir is made from a microporous or nanoporousmaterial. In one embodiment, the composition within said reservoir isreleased through the pores of the reservoir material. In someembodiments, the device comprises a protective sleeve be placed oversaid reservoir. In one embodiment, said sleeve protects against leaksentering the nasal duct or other tissue compartments. In one embodiment,said device contains fluorescent material or coloring to allow fordetection and position confirmation by the user (physician or patient).In one embodiment, said reservoir is implanted within the sinusessurrounding the eye. In one embodiment, the punctal portion or distalend allows for filling the elastic reservoir with medication, but theelastic reservoir sits in a sinus and allows for delivery of drugthrough a microporous balloon. In one embodiment, the punctal portion isimplanted through the caruncle or through the conjunctiva (similar toimplantation of a jones tube) and allow for the microporous balloon pumpto deliver drug directly to the sinus or other tissue areas surroundingthe eye. In another embodiment, the device delivers medication through amicroporous reservoir in addition to the primary embodiment thatdelivers to a tube with a hole positioned at the punctum. In oneembodiment, the reservoir will deliver fluid+/−active ingredients to theocular surface at a fixed rate between 0.1 microliters and 30.0microliters per day for a minimum of one week. In another embodiment,the delivery is achieved for a minimum of 60 days.

Definitions

To facilitate the understanding of this invention, a number of terms aredefined below. Terms defined herein have meanings as commonly understoodby a person of ordinary skill in the areas relevant to the presentinvention. Terms such as “a”, “an” and “the” are not intended to referto only a singular entity, but include the general class of which aspecific example may be used for illustration. The terminology herein isused to describe specific embodiments of the invention, but their usagedoes not delimit the invention, except as outlined in the claims.

As used herein, the term “patient” or “subject” refers to any livingmammalian organism, such as a human, monkey, cow, sheep, goat, dog, cat,mouse, rat, guinea pig, or transgenic species thereof. In certainembodiments, the patient or subject is a primate. Non-limiting examplesof human subjects are adults, juveniles, infants and fetuses.

“Prevention” or “preventing” as used herein, includes, but is notlimited to: (1) inhibiting the onset of a disease in a subject orpatient which may be at risk and/or predisposed to the disease, whereinsuch inhibition may be either partial or complete, but does not yetexperience or display any or all of the pathology or symptomatology ofthe disease, and/or (2) slowing the onset of the pathology orsymptomatology of a disease in a subject or patient which may be at riskand/or predisposed to the disease but does not yet experience or displayany or all of the pathology or symptomatology of the disease.

As used herein, the terms “medication” or “therapeutic agent” refer toany compound and/or molecule that treats or prevents or alleviates thesymptoms of disease or condition, including, but not limited to, a drugor pharmaceutical composition. Medication is considered to be deliveredor present in therapeutically effective amounts or pharmaceuticallyeffective amounts.

“Therapeutically effective amounts” or “pharmaceutically effectiveamounts”, as used herein, means that amount which, when administered toa subject or patient for treating a disease, is sufficient to effectsuch treatment for the disease or to ameliorate one or more symptoms ofa disease or condition (e.g. ameliorate pain).

As used herein, the terms “treat” and “treating” are not limited to thecase where the subject (e.g. patient) is cured and the disease iseradicated. Rather, treatment may also merely reduce symptoms, improves(to some degree) and/or delays disease progression among other effects.It is not intended that treatment be limited to instances wherein adisease or affliction is cured. It is sufficient that symptoms arereduced.

As used herein, the terms “medical device,” “implant,” “device,”“medical device,” “medical implant,” “implant/device,” and the like areused synonymously to refer to any object that is designed to be placedpartially or wholly within a patient's body for one or more therapeuticor prophylactic purposes such as for tissue augmentation, contouring,restoring physiological function, repairing or restoring tissues damagedby disease or trauma, and/or delivering therapeutic agents to normal,damaged or diseased organs and tissues. While medical devices arenormally composed of biologically compatible synthetic materials (e.g.,medical-grade stainless steel, nitinol, titanium and other metals;exogenous polymers, such as polyurethane, silicone, PLA, PLGA, PGA,PCL), other materials may also be used in the construction of themedical implant. While not limiting the present invention to anyparticular device, specific medical devices and implants that areparticularly relevant to this invention include stents, punctal plugs,Crawford tubes, catheters, lacrimal tubes, ocular or other shunts, anddrug delivery systems. In some embodiments, the device incorporates acontrast material or opaque materials that allow for visualization withstandard imaging devices (for example, barium to allow for x-rayvisualization).

As used herein, the term “medication reservoir” refers to any elasticstructure containing medication or therapeutic agent. In preferredembodiments, the reservoir is made of stretchy plastics or silicones.

As used herein, the term “proximal” refers to a location situated towarda point of origin (e.g., between a physician and a lacrimal implantdevice).

As used herein, the term “distal” refers to a location situated awayfrom a point of origin (e.g., behind a lacrimal implant device relativeto a physician).

As used herein, the term “hydrogel” is used to refer to an absorbing orotherwise retaining material (e.g., adsorbing material), such assuper-absorbent polymers, hydrocolloids, and water-absorbent hydrophilicpolymers, for example. In some examples, the term “hydrogel” refers tosuper-absorbent polymer particles in a “dry or dehydrated” state, morespecifically, particles containing from no water up to an amount ofwater less than the weight of the particles, such as less than about 5%,by weight, water. In some examples, the term “hydrogel” refers to asuper-absorbent polymer in the “dry or dehydrated” state when thehydrogel is not expandable and also refers to its hydrated or expandedstate, more specifically, hydrogels that have absorbed at least theirweight in water, such as several times their weight in water. As thehydrogel material absorbs fluid, it size can increase and its shape canchange to bias against at least a portion of a lacrimal canaliculusampulla or lacrimal canaliculus wall, for example.

As used herein, the term “medicament” refers to any active agent that issuitable for use in medical treatment, such as a medicinal compound ordrug.

As used herein, the term “active agent” refers to any molecular entitythat exerts an effect on a living organism.

As used herein, the term “polymer” refers to any organic macromoleculecontaining one or more repeating units, as is well known in the art.

As used herein, a “copolymer” refers to any polymer in which there areat least two types of repeating units included. A copolymer can be ablock copolymer, in which there are segments containing multiplerepeating units of one type, bonded to segments containing multiplerepeating units of a second type.

As used herein, the term “hydrophilic polymer” refers to any polymerthat can be wetted by water, i.e., does not have a water-repellantsurface. A hydrophilic polymer can absorb water to a small degree, forexample about 0-100 wt % of water, but does not greatly swell in volumeas does a hydrogel-forming polymer.

As used herein, the terms “implanted” refers to having completely orpartially placed a device within a host. A device is partially implantedwhen some of the device reaches, or extends to the outside of, a host.

As used herein, the term “steroids” refers to any organic compound thatcontains a core composed of twenty carbon atoms bonded together thattake the form of four fused rings: three cyclohexane rings (designatedas rings A, B, and C in the figure to the right) and one cyclopentanering (the D ring). The steroids vary by the functional groups attachedto this four-ring core and by the oxidation state of the rings. Examplesof steroids include, but are not limited to, the dietary fatcholesterol, the sex hormones estradiol and testosterone, and theanti-inflammatory drug dexamethasone.

As used herein, the term “non-steroidal anti-inflammatory agents,”“nonsteroidal anti-inflammatory drugs,” usually abbreviated to NSAIDs orNAIDs, but also referred to as nonsteroidal anti-inflammatoryagents/analgesics (NSAIAs) or nonsteroidal Anti-inflammatory medicines(NSAIMs), refers to any drug with analgesic and antipyretic(fever-reducing) effects and which have, in higher doses,anti-inflammatory effects.

As used herein, the term “antibiotics” refers to any compound orsubstance that kills or inhibits the growth of bacteria, fungus, orother microorganism.

As used herein, the term “anti-inflammatory agent” refers to anysubstance or treatment that reduces inflammation.

As used herein, the term “immunosuppressant agents” refers to all drugsthat inhibit or prevent activity of the immune system.

As used herein, the term “anti-neoplastic agents” refers to all drugsthat prevent or inhibit the development, maturation, or spread ofneoplastic cells.

As used herein, the term “prostaglandin analogues” refers to allmolecules that bind to a prostaglandin receptor.

As used herein, the term “nitric oxide” or “nitrogen monoxide” refers toany binary diatomic molecule with the chemical formula NO.

As used herein, the term “endothelin” refers to any protein thatconsisting of 21 amino acid residues that are produced in various cellsand tissues, that play a role in regulating vasomotor activity, cellproliferation, and the production of hormones, and that have beenimplicated in the development of vascular disease. For example,endothelin biological activity may include, but is not limited to,constrict blood vessels, raise blood pressure, decrease eye pressure,and protect neuronal tissues from degeneration.

As used herein, the term “corticosteroids” refers to a class ofchemicals that includes any naturally produced steroid hormone orsynthetic steroid hormone analogue. Corticosteroids are involved in awide range of physiologic processes, including, but not limited to,stress response, immune response, and regulation of inflammation,carbohydrate metabolism, protein catabolism, blood electrolyte levels,and behavior.

As used herein, the term “antibody-based immunosuppressants” refers toany antibody (e.g., polyclonal, monoclonal, Fab etc) having animmunosuppressant activity

As used herein, the term “release of an agent” refers to any presence ofthe agent, or a subcomponent thereof, emanating from an implant device.

As used herein, the terms “analogue or analog” refer to any chemicalcompound that is structurally similar to a parent compound but differsslightly in composition (e.g., one atom or functional group isdifferent, added, or removed). An analogue may or may not have differentchemical or physical properties than the original compound and may ormay not have improved biological and/or chemical activity. For example,the analogue may be more hydrophilic, or it may have altered reactivityas compared to the parent compound. The analogue may mimic the chemicaland/or biological activity of the parent compound (i.e., it may havesimilar or identical activity), or, in some cases, may have increased ordecreased activity. The analogue may be a naturally or non-naturallyoccurring (e.g., recombinant) variant of the original compound. Anexample of an analogue is a mutein (i.e., a protein analogue in which atleast one amino acid is deleted, added, or substituted with anotheramino acid). Other types of analogues include isomers (enantiomers,diasteromers, and the like) and other types of chiral variants of acompound, as well as structural isomers. The analogue may be a branchedor cyclic variant of a linear compound. For example, a linear compoundmay have an analogue that is branched or otherwise substituted to impartcertain desirable properties (e.g., improve hydrophilicity orbioavailability).

As used herein, the term “derivative” refers to any chemically orbiologically modified version of a chemical compound that isstructurally similar to a parent compound and (actually ortheoretically) derivable from that parent compound. A “derivative”differs from an “analogue” in that a parent compound may be the startingmaterial to generate a “derivative,” whereas the parent compound may notnecessarily be used as the starting material to generate an “analogue.”An analogue may have different chemical or physical properties of theparent compound. For example, the derivative may be more hydrophilic orit may have altered reactivity as compared to the parent compound.Derivatization (i.e., modification) may involve substitution of one ormore moieties within the molecule (e.g., a change in functional group).For example, a hydrogen may be substituted with a halogen, such asfluorine or chlorine, or a hydroxyl group (—OH) may be replaced with acarboxylic acid moiety (—COOH). The term “derivative” also includesconjugates, and prodrugs of a parent compound (i.e., chemically modifiedderivatives that can be converted into the original compound underphysiological conditions). For example, the prodrug may be an inactiveform of an active agent. Under physiological conditions, the prodrug maybe converted into the active form of the compound. Prodrugs may beformed, for example, by replacing one or two hydrogen atoms on nitrogenatoms by an acyl group (acyl prodrugs) or a carbamate group (carbamateprodrugs). More detailed information relating to prodrugs is found, forexample, in Fleisher et al., Advanced Drug Delivery Reviews 19 (1996)115 [1] incorporated herein by reference. The term “derivative” is alsoused to describe all solvates, for example hydrates or adducts (e.g.,adducts with alcohols), active metabolites, and salts of the parentcompound. The type of salt that may be prepared depends on the nature ofthe moieties within the compound. For example, acidic groups, forexample carboxylic acid groups, can form, for example, alkali metalsalts or alkaline earth metal salts (e.g., sodium salts, potassiumsalts, magnesium salts and calcium salts, and also salts withphysiologically tolerable quaternary ammonium ions and acid additionsalts with ammonia and physiologically tolerable organic amines such as,for example, triethylamine, ethanolamine or tris-(2-hydroxyethyl)amine).Basic groups can form acid addition salts, for example with inorganicacids such as hydrochloric acid, sulfuric acid or phosphoric acid, orwith organic carboxylic acids and sulfonic acids such as acetic acid,citric acid, benzoic acid, maleic acid, fumaric acid, tartaric acid,methanesulfonic acid or p-toluenesulfonic acid. Compounds thatsimultaneously contain a basic group and an acidic group, for example acarboxyl group in addition to basic nitrogen atoms, can be present aszwitterions. Salts can be obtained by customary methods known to thoseskilled in the art, for example by combining a compound with aninorganic or organic acid or base in a solvent or diluent, or from othersalts by cation exchange or anion exchange.

As used herein, the term “inhibitor” or “antagonist” refers to any agentthat prevents a biological process from occurring and/or slows the rateand/or slows the degree of occurrence of a biological process. Theprocess may be a general one such as scarring or refer to a specificbiological action such as, for example, a molecular process resulting inrelease of a cytokine.

As used herein, the term “agonist” refers to any agent that stimulates abiological process or rate or degree of occurrence of a biologicalprocess. The process may be a general one such as scarring or refer to aspecific biological action such as, for example, a molecular processresulting in release of a cytokine.

As used herein, the term “anti-microtubule agent” should be understoodto include any protein, peptide, chemical, or other molecule thatimpairs the function of microtubules, for example, through theprevention or stabilization of polymerization. Compounds that stabilizepolymerization of microtubules are referred to herein as “microtubulestabilizing agents.” A wide variety of methods may be utilized todetermine the anti-microtubule activity of a particular compound,including for example, assays described by Smith et al. (Cancer Lett.79(2):213-219, 1994) [2] and Mooberry et al., (Cancer Lett.96(2):261-266, 1995) [3] both incorporated herein by reference.

Any concentration ranges, percentage range, or ratio range recitedherein are to be understood to include concentrations, percentages orratios of any integer within that range and fractions thereof, such asone tenth and one hundredth of an integer, unless otherwise indicated.In addition, any number range recited herein relating to any physicalfeature, such as polymer subunits, size or thickness, are to beunderstood to include any integer within the recited range, unlessotherwise indicated. It should be understood that the terms “a” and “an”as used above and elsewhere herein refer to “one or more” of theenumerated components. For example, “a” polymer refers to both onepolymer or a mixture comprising two or more polymers. As used herein,the term “about” means±15%.

As used herein, the term “biomaterial” refers to any substance (otherthan drugs) or combination of substances synthetic or natural in origin,which can be used for any period of time, as a whole or as a part of asystem which treats, augments, or replaces any tissue, organ, orfunction of the body.

As used herein, the term “biocompatibility” refers to the ability of amaterial to perform with an appropriate host response in a specificapplication.

As used herein, the term “elastic limit” or “yield strength” refers tothe stress at which a material begins to deform plastically. Prior tothe yield point the material will deform elastically and will return toits original shape when the applied stress is removed. Once the yieldpoint is passed, some fraction of the deformation will be permanent andnon-reversible.

As used herein, the term “elastic” refers to a material that with verylarge deformability when forces are applied on it with completerecoverability, meaning the object will return to its initial shape andsize when these forces are removed. Such a feature has also beenreferred to as rubber elasticity. Molecular Requirements of such“elastic” materials: Material must consist of polymer chains, Need tochange conformation and extension under stress. Polymer chains must behighly flexible. Need to access conformational changes (not w/glassy,crystalline, stiff mat.) Polymer chains must be joined in a networkstructure. Need to avoid irreversible chain slippage (permanent strain).One out of 100 monomers must connect two different chains. Connections(covalent bond, crystallite, glassy domain in block copolymer) Examplesof elastic polymers include rubber, latex, synthetic rubbers, neoprene,silicone and the like.

As used herein, the term “non-elastic” refers to a material that withlow or no deformability when forces are applied on it. Beyond the strainlimit, a non-elastic material will experience irreversible deformation.Polymer chains are not flexible and do not easily access conformationalchanges. These may undergo irreversible chain slippage (permanentstrain) Examples include glass, hard plastics, amorphous glassy polymersand the like.

As used herein, the term “semi-elastic” refers to a material that withmoderate deformability when forces are applied on it with completerecoverability, meaning the object will return to its initial shape andsize when these forces are removed. There are a number of semi-elasticpolymers. Examples of semi-crystalline polymers are linear polyethylene(PE), polyethylene terephthalate (PET), polytetrafluoroethylene (PTFE)or isotactic polypropylene (PP).

As used herein, the term “self-compression” refers to when a material isadded to a reservoir and filled to distortion leading to elastic forcesto compress material inside the reservoir. This self-compressionprovides a force to initiate distribution of the material within thereservoir out of the reservoir, either through a flow limiting port orthrough forced diffusion.

As used herein, the term “stent” refers to any artificial ‘tube’inserted into a natural passage/conduit in the body to prevent, orcounteract, a disease-induced, localized flow constriction. The term mayalso refer to a tube used to temporarily hold such a natural conduitopen to allow access for surgery.

As used herein, the term “shunt” refers to any artificial ‘tube’inserted into the body to create a hole or passage to allow movement offluids between two areas. Said tube may be implanted temporarily or maybe permanent.

As used herein, the term “Foley catheter” refers to a flexible tube thatis often passed through the urethra and into the bladder. The tube hastwo separated channels, or lumens, running down its length. One lumen isopen at both ends, and allows urine to drain out into a collection bag.The other lumen has a valve on the outside end and connects to a balloonat the tip; the balloon is inflated with sterile water, or otherfluid/gas, when it lies inside the bladder, in order to stop it fromslipping out.

As used herein, the term “catheter” refers to any tube that can beinserted into a body cavity, duct, or vessel. Catheters thereby allowdrainage, administration of fluids or gases, or access by surgicalinstruments. The process of inserting a catheter is catheterization. Inmost uses, a catheter is a thin, flexible tube (“soft” catheter), thoughin some uses, it is a larger, solid (“hard”) catheter. A catheter leftinside the body, either temporarily or permanently, may be referred toas an indwelling catheter. A permanently inserted catheter may bereferred to as a permcath.

As used herein, the term “microelectromechanical systems” or “MEMS”refers to technology of very small devices. MEMS are separate anddistinct from the hypothetical vision of molecular nanotechnology ormolecular electronics. MEMS are made up of components between 1 to 100micrometres in size (i.e. 0.001 to 0.1 mm), and MEMS devices generallyrange in size from 20 micrometres (20 millionths of a metre) to amillimetre (i.e. 0.02 to 1.0 mm). They usually consist of a central unitthat processes data (the microprocessor) and several components thatinteract with the surroundings such as microsensors.

As used herein, the term “PLGA or poly(lactic-co-glycolic acid)” refersto a copolymer and is approved for therapeutic devices by the UnitedStates Food and Drug Administration (FDA), owing to its biodegradabilityand biocompatibility. PLGA has been studied for slow drug release [4].

As used herein, the term “polyethylene glycol” (abbreviated PEG) refersto any polyether compound. For example, PEG is commercially available aspolyethylene oxide (PEO) or polyoxyethylene (POE), depending on itsmolecular weight (Carbowax®).

DESCRIPTION OF THE FIGURES

The accompanying figures, which are incorporated into and form a part ofthe specification, illustrate several embodiments of the presentinvention and, together with the description, serve to explain theprinciples of the invention. The figures are only for the purpose ofillustrating a preferred embodiment of the invention and are not to beconstrued as limiting the invention.

FIGS. 1A and 1B show an example of currently used punctal plugs insertedinto the inferior punctum (FIG. 1B showing a partial enlargement of FIG.1A). Some punctal plugs are used a medication release platforms, butcontain a very limited reservoir and depend upon natural interactionwith the tear film and tear distribution for dispersal of thetherapeutic agent.

FIGS. 2A and 2B show an example of the current invention's design. Thismodel shows both an inflated (FIG. 2B) and depressed (FIG. 2A)reservoir. This device provides for the controlled release of thetherapeutic agent via a flow limited port attached to the tube portionthat exits a punctum of the lacrimal system (shown in FIG. 3A-F).

FIG. 3A-F shows examples of the inflated device properly inserted withinthe lacrimal system, portion of the lacrimal system, and the inflateddevice by itself. FIG. 3A shows the inflated device by itself. FIG. 3Bshows the major parts of the lacrimal system with which the deviceinteracts. FIG. 3C shows an embodiment of the device, where there aretwo sets of tubes extending through each lacrimal duct to each punctum(superior punctum and an inferior punctum, upper punctum and a lowerpunctum, respectively). The device may have one or two sets of tubes.FIG. 3D show an embodiment of the device with two sets of tubes, butwithout the third flushing/refilling tube. FIG. 3E shows a preferredembodiment, a device with a single set of tubes terminating in a flowlimiting port 5, said port terminates in the upper (superior) punctum.FIG. 3F shows the device with a single set of tubes terminating in aflow limiting port 5, said port terminates in the lower (inferior)punctum.

FIG. 4 shows a diagram of the lacrimal system. Herein, the upper andlower lacrimal ducts converge into the naso-lacrimal duct. The device isenvisioned to extend from the reservoir located in the lacrimal sac andextend from the reservoir via tube into either the upper or lowerlacrimal duct terminating in a puncta lacrimalia (a punctum) with a flowlimiting port 5.

FIG. 5 shows an angled view of the device.

FIG. 6 shows an angled view of the device.

FIG. 7 shows a tube distal end close-up.

FIGS. 8A & B show one embodiment of the device. FIG. 8A shows the deviceconsisting of a microporous balloon 1 that can deliver drug directly totissue spaces such as sinuses. In contains a tube (3, 2) with a flowlimiting port/exit port 5 which may or may not contain a distal membrane7 which can serve as a simple filling port 7 (located in the punctum orin the conjunctiva/caruncle or surrounding tissues) to refill themicroporous balloon 1 as needed. The balloon 1 then oozes outmedication/fluid to targeted tissues. FIG. 8B shows that a nitinol cage13 or other structural features may serve to exert pressure on themicroporous balloon/reservoir 1.

FIG. 9 shows a device where there is a microporous balloon/elasticreservoir 1 and a distal membrane 7 where the first tube 2 contains bioerodible elements 6, and an internal plunger 8, and an exit port 9 isconnected to internal springs 10 connected to said internal plunger 8,microelectromechanical systems spring pressure regulator 12, andbioerodible materials 6 open up inlet pores sequentially allowing alongsaid internal composition column which would enable for pulsed dosing ofthe active agent composition.

FIG. 10 shows one embodiment of the device where a separate nitinoldevice 13 is constructed to surround the reservoir 1 prior to filling sothat the nitinol cage 13 contains straight wires. Once filled, thereservoir 1 pushes the nitinol out and the nitinol then acts on thenon-elastic or semi-elastic material to slowly push fluid out towardsthe flow limiting membrane 7 at the top (exit port 9).

LIST OF REFERENCE NUMERALS

-   1 elastic reservoir-   2 first tube-   3 second tube-   4 third tube-   5 faceplate containing flow limiting capabilities-   6 bio erodible elements-   7 distal membrane-   8 internal plunger-   9 exit port-   10 internal springs-   11 internal plunger-   12 microelectromechanical systems spring pressure regulator-   13 nitinol cage

DETAILED DESCRIPTION

In order to eye treat infection, inflammation of the eye, glaucoma andother ocular diseases or disorders, drugs are often required to beadministered to the eye. A conventional method of drug delivery is bytopical drop application to the eye's surface. Topical eye drops, thougheffective, can be inefficient. As one example, when an eye drop isinstilled in an eye, it often overfills the conjunctival sac (i.e., thepocket between the eye and the lids) causing a substantial portion ofthe drop to be lost due to overflow of the lid margin and spillage ontothe cheek. In addition, a large portion of the drop remaining on theocular surface can be washed away into and through a lacrimalcanaliculus, thereby diluting the concentration of the drug before itcan treat the eye. Moreover, topically applied drugs often have a peakocular effect for about two hours post-application, after whichadditional applications of the drugs should be, but are often not,administered to maintain the desired drug therapeutic benefit.

To compound ocular management difficulty, patients often do not usetheir eye drops as prescribed. This poor compliance can be due to, forexample, an initial stinging or burning sensation caused by the eye dropand experience by a patient. Instilling eye drops in one's own eye canbe difficult, in part because of the normal reflex to protect the eye.Therefore, one or more drops may miss the eye. Older patients may haveadditional problems instilling drops due to arthritis, unsteadiness, anddecreased vision. Pediatric and psychiatric populations posedifficulties as well.

Conditions of dry eye have been treated by blocking the tear flow fromthe eye into and through the lacrimal canaliculus. This has involvedclosing the canalicular canal by stitching the punctal opening shut orby using electrical or laser cauterization to seal the punctal opening.Although such procedures can provide the desired result of blocking tearflow to treat a dry eye, they are unfortunately not reversible withoutreconstructive surgery.

In a field different from ocular management, control ofrespiration-related (e.g., allergies) diseases or disorders oftenrequires repetitive manual digestion or other intake of a medication,and as such, can be ineffective due to a lack of patient compliance ornon-localized drug delivery.

Therapeutic Devices

There have a variety of therapeutic devices designed to address eye andlacrimal system related conditions. Primary amongst them are lacrimalpunctal plugs. There are several devices, which have useful features,yet do not have the advantages of the current invention.

In one reference, Sim, S. et al. “Composite Lacrimal Insert and RelatedMethods,” United States Patent Application 20100034870 application Ser.No. 12/432,553, filed Apr. 29, 2009 [5], discloses a removable,drug-releasing lacrimal implant owned by QLT. The plug is implanted intoa lacrimal punctum of a subject. Such a punctal plug comprise to a drugcore that erodes with delivery to the tear film, dependent on tearmovement to dissolution of the drug core. The drug core is sedentary andthe tears are required to flow in and out of the reservoir for drugdistribution. This application does not teach the elastic reservoirsystem and the active “pushing” of fluid into the tear film of thecurrent invention.

In another reference, Hubbell, J. A. et al. “PhotopolymerizableBiodegradable Hydrogels as Tissue Contacting Materials andControlled-Release Carriers,” U.S. Pat. No. 5,410,016 filed Mar. 1, 1993[6], discloses a biodegradable PEG based system also used for punctalplug delivery owned by Ocular Therapeutix. This does not describe thedevice with an elastic reservoir of the current invention.

In another reference, Rodstrom, T. R. et al. “Punctal Plugs and Methodsof Delivering Therapeutic Agents,” United States Patent Application20080181930 filed Jan. 30, 2008 [7], discloses another punctal plug drugdelivery system with a matrix of a silicone and an ophthalmic drug witha parylene polymer coating on a portion of the outer surface. The methodof drug delivery is passive utilizing the dissolution of the drug intothe tear film of the eye. The plug and an extended portion, but lacksthe reservoir of the current invention.

In another reference, Borgia, M. J. et al. “Punctal Plugs for theDelivery of Active Agents,” United States Patent Application 20070298075filed Jun. 7, 2007 [8], discloses another example of punctal plugs withslow release drug delivery. The reference does not describe reservoir ofthe current invention.

In another reference, Beeley, N. R. F. and Coldren, B. A. “Punctal Plugsfor Controlled Release of Therapeutic Agents,” United States PatentApplication 20110251568 filed Mar. 8, 2011 [9], discloses several typesof punctal plugs, but in one example, the plug includes an extended“reservoir” which is to be slightly permeable and extends into thelacrimal ducts. The reference does not describe an elastic reservoir ora reservoir located in the lacrimal sac of the current invention.

In another reference, Brubaker, M. J. et al. “Sustained Release DrugDelivery Devices,” WIPO Patent Application WO/2002/056863 ApplicationPCT/US2001/048804, filed Jul. 25, 2002 [10], discloses another plugdevice for distribution of a medication. The reference does not describean elastic reservoir or a reservoir located in the lacrimal sac of thecurrent invention.

In another reference, Rapacki, A. R. et al. “Lacrimal Implants andRelated Methods,” United States Patent Application 20100274204 filedFeb. 23, 2010 [11], discloses another lacrimal drug delivery devicewhich is an extended version of a punctal plug, with an additionalanchoring arm that extends down the lacrimal duct when inserted. Thereference describes the use of “balloons” as structural elements toposition the device, not as drug containing reservoirs. The referencedoes not describe an elastic reservoir or a reservoir located in thelacrimal sac of the current invention.

In another reference, Cohan, B. E. “Opthalmic Insert and Method forSustained Release of Medication to the Eye,” European Patent EP1891942B1Application EP1178779A1, filed Apr. 7, 2000 [12], discloses an apparatusfor intubation of lacrimal duct (lacrimal drainage pathway) fortreatment of lacrimal duct obstruction. Additionally, the internalportion of the device may act as a reservoir of medication that may bereleased through a pore on the device in a controlled manner based upona specific geometry of the device. This controlled rate is still basedupon tear dissolution of the medication and penetration of the reservoirby the tear film. The reference does not describe an elastic reservoiror a reservoir located in the lacrimal sac of the current invention.

In another reference, Murube, J. et al. (2003) Subcutaneous AbdominalArtificial Tears Pump-Reservoir for Severe Dry Eyes, Orbit 22(1), 29[13], discloses a study of an implanted pump-reservoir unit placed underthe subcutaneous tissue of the abdomen for providing artificial tears tothe ocular surface in patients with severe dry eye. While this systemdoes provide for a reservoir, the system uses an electrical pump and thereservoir's location is far from the lacrimal sac. The reference doesnot describe an elastic reservoir or a reservoir located in the lacrimalsac of the current invention.

DETAILED DESCRIPTION OF A PREFERRED EMBODIMENT

The current invention involves an implanted medical device designed as alacrimal system drug delivery device. It is a lacrimal system devicewith associated flexible elastic reservoir can be implanted so that thedistal edge is proximate to the tear film abutting the upper or lowerpunctum and the opposite end is composed of a flexible material thatforms an elastic reservoir (positioned in the lacrimal sac) that can befilled with an active ingredient, such as a drug or other therapeuticsolution. Once filled, the active ingredient will be “pushed” from theelastic reservoir to the distal opening, which is proximate to the tearfilm. The drug then enters the tear film and is absorbed by eye tissuesto treat various ocular diseases. The device may or may not also connectto the nasal cavity through the termination of the tear duct system. Theegress of drug from the balloon of the device is entirely dependent onthe elastic reservoir's effort to return to the uninflated state. Noactive pumps are needed. The ultimate goal of this device is to deliverdrugs long term to the ocular surface in a regular and consistentmanner. Other devices that deliver drug to the tear film using a punctalplug or lacrimal plug do so by a drug core that degrades after contactwith the tear film.

While not limiting the current invention, one method of insertion of thedevice would be to introduce the collapsed device on the punctal side inan insertion method similar to the introduction of a Crawford tube. Thecollapsed reservoir of the device is envisioned to fit through thepunctum and canaliculus wherein the reservoir of the device would residein the lacrimal sac allowing for expansion when filled with atherapeutic agent. In one embodiment, a lubricant is coupled with thesystem to allow for smoother atraumatic insertion. In the embodiment,the device contains a further tube from the reservoir allowing access tothe reservoir from the nasolacrimal duct for flushing and refilling. Inone embodiment, a further tube could be accessed through various meansincluding, but not limited to a small clip upon the tube, a groove ingroove lock system, a kiss lock/coin purse system of closure, orcomplete closure or crimping of the end of the tube. While not limitingthe device, it is envisioned that the device would conform the standardanatomical size variations. In one embodiment, the device could be usedfor subjects of various sizes and age ranges. In one embodiment, thedevice may not be appropriate in certain subjects, including, but notlimited to subjects with trauma to the nasolacrimal system, subjectswith chronic nasal inflammation, or dacryocystitis. Dacryocystitis is aninflammation of the nasolacrimal sac, frequently caused by nasolacrimalduct obstruction or infection. In one embodiment, the device functionsand serves for at least two months or greater than sixty days. In theparticular cases of treating dye eye or glaucoma, the device therapywould last at least two months. In the case of post-surgical treatmentof conditions, such as cataracts, would involve treatment ranging of twoto six week, possibly longer.

One embodiment of the device design standing alone as shown in FIGS. 2Aand 2B, and implanted in the lacrimal system as shown in FIGS. 3A-3F.FIGS. 2A and 2B and FIGS. 3A-3F shows an elastic reservoir 1 having aloading port and an exit port that can be filled and flushed andrefilled . . . etc. This can be made of stretchy plastics or silicones.The therapeutic agent reside in both the reservoir 1 and the third tube4 connected to said loading port prior to moving through the first tube2 connected to said exit port and the second tube 3 comprising a flowlimiting port 5 connected to said first tube 2. In one embodiment, saidflow limiting port 5 is a faceplate containing flow limitingcapabilities. In one embodiment, the first and second tube comprise onecontinuous tube connected to the exit port of the reservoir 1terminating in said flow limiting port 5. In one embodiment, said flowlimiting port 5 comprises a distal membrane 7. In one embodiment, asdemonstrated in FIGS. 3A-3F, the device comprises a second set of first2 and second tubes 3 connected to the exit port of the reservoir 1terminating in said flow limiting port 5. The third tube 4 is aconnection to the nasal cavity through the nasolacrimal duct to allowfor flushing of the elastic reservoir 1 or refilling of same. Theterminal end of the third tube 4 can be clipped closed or pinched to bewatertight. The second tube 3 is open to external punctum and tear film.A valve mechanism or small caliber opening will control flow of thefluid from this distal faceplate to the tear film; this is referred toas the flow limiting port 5. The rate of flow can be altered bymodifying the elastic reservoir characteristics and/or the distal flowlimiting mechanism at the faceplate. The first tube 2 is the canalicular(to be inserted in the lacrimal canal) portion of device contains lumenconnecting the elastic reservoir 1 to the second tube 3 and to the tearfilm.

In one embodiment, the balloon component 1 of the device may be designedonly for fixation and not delivery (like foley catheter retentionfeature). In one embodiment, nitinol wire (or other material) springs 10are used internal to the lacrimal portion of the device that pulls aninternal plunger 8 towards the distal opening as fluid is released toallow for constant fluid delivery without relying on a constant pressureelastomeric balloon 1. In one embodiment, the device comprisesbioerodible or biodegradable materials 6. In one embodiment, saidbioerodible 6 or biodegradable materials 6 open up inlet poressequentially allowing along the internal fluid column which would enablefor pulsed dosing. In one embodiment, the device further comprises amicroelectromechanical systems (MEMS) spring pressure regulator 12. Inone embodiment, ePTFE membranes 7 may be used to regulate flow out ofthe distal end of said device. In one embodiment, such a distal membrane7 will control flow of the fluid from this distal faceplate to the tearfilm; this is referred to as the flow limiting port 5. For example,ePTFE with 0.0003″+/−0.0001″ (0.00762 mm+/−0.00254 mm) thickness andwith a porosity of 80%+/−10% and a mean flow pore size of 0.2 to 0.5micron. In one embodiment, one or more layers of ePTFE material can beused for flow regulation. FIG. 5 shows an angled view of the device.FIG. 6 shows an angled view of the device. FIG. 7 shows a tube distalend close-up. FIG. 8A & B show one embodiment of the device. FIG. 8Ashows the device consisting of a microporous balloon 1 that can deliverdrug directly to tissue spaces such as sinuses. In contains a tube (2,3) with a flow limiting port/exit port 5 which may or may not contain adistal membrane 7 which can serve as a simple filling port 7 (located inthe punctum or in the conjunctiva/caruncle or surrounding tissues) torefill the microporous balloon 1 as needed. The balloon 1 then oozes outmedication/fluid to targeted tissues. FIG. 8B shows that a nitinol cage13 or other structural features may serve to exert pressure on themicroporous balloon/reservoir 1. Instead of drug/composition beingdelivered only through the distal membrane 7 or flow limiting port 5,this option provides the capability to deliver drug directly from thereservoir 1 to surrounding tissues with or without delivery through thedistal part as well. There are certain diseases that would benefit fromthis approach, like chronic sinusitis. FIG. 9 shows a device where thereis a microporous balloon/elastic reservoir 1 and a distal membrane 7where the first tube 2 contains bio erodible elements 6, and an internalplunger 8, and an exit port 9 is connected to internal springs 10connected to said internal plunger 8, microelectromechanical systemsspring pressure regulator 12, and bioerodible materials 6 open up inletpores sequentially allowing along said internal composition column whichwould enable for pulsed dosing of the active agent composition. FIG. 10shows one embodiment of the device where a separate nitinol device 13 isconstructed to surround the reservoir 1 prior to filling so that thenitinol cage 13 contains straight wires. Once filled, the reservoir 1pushes the nitinol out and the nitinol then acts on the non-elastic orsemi-elastic material to slowly push fluid out towards the flow limitingmembrane 7 at the top (exit port). In one embodiment, the elasticreservoir 1 will deliver fluid+/−active ingredients to the ocularsurface at a fixed rate between 0.1 microliters and 30.0 microliters perday for a minimum of one week. In another embodiment, the delivery isachieved for a minimum of 60 days.

In one embodiment the device comprises a reservoir 1 and a first tube.In one embodiment, the device comprises a nonelastic reservoir 1 that iscontained within surrounding material that allows for compression ofsaid reservoir 1. In one embodiment, a nitinol wire, spring or cage 13may be used to provide the compression of said reservoir 1. In oneembodiment, the reservoir 1 is substantially nonelastic. In oneembodiment, said reservoir 1 is made from a microporous or nanoporousmaterial. In one embodiment, the composition within said reservoir 1 isreleased through the pores of the reservoir material. In someembodiments, the device comprises a protective sleeve be placed oversaid reservoir. In one embodiment, said sleeve protects against leaksentering the nasal duct or other tissue compartments. In one embodiment,said device contains fluorescent material or coloring to allow fordetection and position confirmation by the user (physician or patient).In one embodiment, said reservoir is implanted within the sinusessurrounding the eye. In one embodiment, the punctal portion or distalend allows for filling the elastic reservoir with medication, but theelastic reservoir 1 sits in a sinus and allows for delivery of drugthrough a microporous balloon. In one embodiment, the punctal portion isimplanted through the caruncle or through the conjunctiva (similar toimplantation of a jones tube) and allow for the microporous balloon pumpto deliver drug directly to the sinus or other tissue areas surroundingthe eye. In another embodiment, the device delivers medication through amicroporous reservoir in addition to the primary embodiment thatdelivers to a tube with a hole positioned at the punctum.

As discussed above, the present invention provides compositions, methodsand devices relating to a lacrimal, eye, sinuses and/or perioculartissues system implant devices, which greatly increase their ability todeliver therapeutic agents consistently with a simple straightforwarddesign and in larger quantities than is currently available. In oneaspect, the present invention provides for the combination of varioustherapeutic agents and lacrimal, eye, sinuses and/or periocular tissuessystem implant for use in medical intervention, continuing medicaltherapy, and/or cosmetic or reconstructive surgery. In one aspect, thepresent invention is a lacrimal, eye, sinuses and/or periocular tissuessystem therapeutic agent delivery device for use in medicalintervention, continuing medical therapy, and/or cosmetic orreconstructive surgery.

In some examples, an antimicrobial coating can be disposed on, orimpregnated in, at least a portion of the outer surface of the implantbody to further prevent microbial growth on the implant body. In anexample, the antimicrobial coating can include an agent selected fromthe group comprising 2-bromo-2-nitropropane-1,3-diol,5-bromo-5-nitro-1,3-dioxane, 7-ethyl bicyclooxazolidine, benzalkoniumchloride, benzethonium chloride, benzoic acid, benzyl alcohol, boricacid, bronopol, cetylpyridinium chloride, chlorhexidine digluconate,chloroacetamide, chlorobutanol, chloromethyl isothiazolinone and methylisothiazoline, dimethoxane, dimethyl oxazolidine, dimethyl hydroxymethylpyrazole, chloroxylenol, dehydroacetic acid, diazolidinyl urea,dichlorobenzyl alcohol, DMDM hydantoin, ethyl alcohol, formaldehyde,glutaraldehyde, hexachlorophene, hexetidine, hexamethylenetramine,imidazolidinyl urea, iodopropynyl butylcarbamate, isothiazolinones,methenammonium chloride, methyldibromo glutaronitrile, MDM hydantoin,minocycline, ortho phenylphenol, p-chloro-m-cresol, parabens(butylparaben, ethylparaben, methylparaben), phenethyl alcohol,phenoxyethanol, piroctane olamine, polyaminopropyl biguanide,polymethoxy bicyclic oxazolidine, polyoxymethylene, polyquaternium-42,potassium benzoate, potassium sorbate, propionic acid, quaternium-15,rifampin, salicylic acid, selenium disulfide, sodium borate, sodiumiodate, sodium hydroxymethylglycinate, sodium propionate, sodiumpyrithione, sorbic acid, thimerosal, triclosan, triclocarban,undecylenic acid, zinc phenosulfonate, and zinc pyrithione. In anexample, the antimicrobial coating can include a material selected fromthe group comprising silver lactate, silver phosphate, silver citrate,silver acetate, silver benzoate, silver chloride, silver iodide, silveriodate, silver nitrate, silver sulfadiazine, silver palmitate or one ormore mixtures thereof. In an example, the antimicrobial coating caninclude at least one of an antibiotic or an antiseptic. For instance,the antimicrobial coating can include a temporary anesthetic lasting, onaverage, between a few hours and a day. In still other examples, theantimicrobial coating can include a drug use to treat an underlyingdisease, such as a bolus for immediate effect.

A therapeutic agent (or simply “agent”) can comprise, among otherthings, a drug made from one or any combination of the following ortheir equivalents, derivatives or analogs, including, anti-glaucomamedications, (e.g. adrenergic agonists, adrenergic antagonists (betablockers), carbonic anhydrase inhibitors (CAIs, systemic and topical),parasympathomimetics, prostaglandins and hypotensive lipids, andcombinations thereof), antimicrobial agent (e.g., antibiotic, antiviral,antiparacytic, antifungal, etc.), a corticosteroid or otheranti-inflammatory (e.g., an NSAID or other analgesic and pain managementcompounds), a decongestant (e.g., vasoconstrictor), an agent thatprevents of modifies an allergic response (e.g., an antihistamine,cytokine inhibitor, leucotriene inhibitor, IgE inhibitor,immunomodulator), a mast cell stabilizer, cycloplegic, mydriatic or thelike.

Example available agents include, but are not limited to, thrombininhibitors; antithrombogenic agents; thrombolytic agents; fibrinolyticagents; vasospasm inhibitors; vasodilators; antihypertensive agents;antimicrobial agents, such as antibiotics (such as tetracycline,chlortetracycline, bacitracin, neomycin, polymyxin, gramicidin,cephalexin, oxytetracycline, chloramphenicol, rifampicin, ciprofloxacin,tobramycin, gentamycin, erythromycin, penicillin, sulfonamides,sulfadiazine, sulfacetamide, sulfamethizole, sulfisoxazole,nitrofurazone, sodium propionate), antifungals (such as amphotericin Band miconazole), and antivirals (such as idoxuridine trifluorothymidine,acyclovir, gancyclovir, interferon); inhibitors of surface glycoproteinreceptors; antiplatelet agents; antimitotics; microtubule inhibitors;anti-secretory agents; active inhibitors; remodeling inhibitors;antisense nucleotides; anti-metabolites; antiproliferatives (includingantiangiogenesis agents); anticancer chemotherapeutic agents;anti-inflammatories (such as hydrocortisone, hydrocortisone acetate,dexamethasone 21-phosphate, fluocinolone, medrysone, methylprednisolone,prednisolone 21-phosphate, prednisolone acetate, fluoromethalone,betamethasone, triamcinolone, triamcinolone acetonide); non steroidalanti-inflammatories (NSAIDs) (such as salicylate, indomethacin,ibuprofen, diclofenac, flurbiprofen, piroxicam indomethacin, ibuprofen,naxopren, piroxicam and nabumetone). Examples of such anti-inflammatorysteroids contemplated for use with the present lacrimal implants,include triamcinolone acetonide (generic name) and corticosteroids thatinclude, for example, triamcinolone, dexamethasone, fluocinolone,cortisone, prednisolone, flumetholone, and derivatives thereof.);antiallergenics (such as sodium chromoglycate, antazoline,methapyriline, chlorpheniramine, cetrizine, pyrilamine,prophenpyridamine); anti proliferative agents (such as 1,3-cis retinoicacid, 5-fluorouracil, taxol, rapamycin, mitomycin C and cisplatin);decongestants (such as phenylephrine, naphazoline, tetrahydrazoline);miotics and anti-cholinesterase (such as pilocarpine, salicylate,carbachol, acetylcholine chloride, physostigmine, eserine, diisopropylfluorophosphate, phospholine iodine, demecarium bromide);antineoplastics (such as carmustine, cisplatin, fluorouracil;immunological drugs (such as vaccines and immune stimulants); hormonalagents (such as estrogens,—estradiol, progestational, progesterone,insulin, calcitonin, parathyroid hormone, peptide and vasopressinhypothalamus releasing factor); immunosuppressive agents, growth hormoneantagonists, growth factors (such as epidermal growth factor, fibroblastgrowth factor, platelet derived growth factor, transforming growthfactor beta, somatotrapin, fibronectin); inhibitors of angiogenesis(such as angiostatin, anecortave acetate, thrombospondin, anti-VEGFantibody); dopamine agonists; radiotherapeutic agents; peptides;proteins; enzymes; extracellular matrix; components; ACE inhibitors;free radical scavengers; chelators; antioxidants; anti polymerases;photodynamic therapy agents; gene therapy agents; and other therapeuticagents such as prostaglandins, antiprostaglandins, prostaglandinprecursors, including antiglaucoma drugs including beta-blockers such asTimolol, betaxolol, levobunolol, atenolol, and prostaglandin analoguessuch as bimatoprost, travoprost, latanoprost etc; carbonic anhydraseinhibitors such as acetazolamide, dorzolamide, brinzolamide,methazolamide, dichlorphenamide, diamox; and neuroprotectants such aslubezole, nimodipine and related compounds; and parasympathomimetricssuch as pilocarpine, carbachol, physostigmine and the like.

Additional agents that can be used with the present lacrimal implantsinclude, but are not limited to, drugs that have been approved underSection 505 of the United States Federal Food, Drug, and Cosmetic Act orunder the Public Health Service Act. The present lacrimal implants canalso be used with drugs listed in the FDA Orange Book that has orrecords the same date as, earlier date than, or later date than, thefiling date of this patent document. For example, these drugs caninclude but are not limited to, among others, dorzolamide, olopatadine,travoprost, bimatoprost, cyclosporin, brimonidine, moxifloxacin,tobramycin, brinzolamide, aciclovir timolol maleate, ketorolactromethamine, prednisolone acetate, sodium hyaluronate, nepafenac,bromfenac, diclofenac, flurbiprofen, suprofenac, binoxan, patanol,dexamethasone/tobramycin combination, moxifloxacin, or acyclovir.

Examples of diseases or disorders that can be treated with above-listedagents include, but are not limited to, glaucoma, pre- and post-surgicalocular treatments, dry eye, anti-eye allergy, anti-infective,post-surgical inflammation or pain, or respiration-related disorders,such as allergies In some examples, the therapeutic agent can include alubricant or a surfactant, for example a lubricant to treat dry eye. Inother examples, the therapeutic agent can include an absorbent capableof absorbing tear from an eye.

Although the form of the therapeutic agent is envisioned to be a liquidwith a flow limited release through a port connected to the reservoir,is also possible that the drug supply can comprise one or morebiocompatible materials capable of providing a sustained release of theone or more agents. For example, a biodegradable matrix, a porous drugsupply, or liquid drugs supply. A matrix that includes the agents can beformed from either biodegradable or non-biodegradable polymers. In someexamples, a non-biodegradable drug supply can include, but are notlimited to, silicone, acrylates, polyethylenes, polyurethane,polyurethane, hydrogel, polyester (e.g., DACRON® from E. I. Du Pont deNemours and Company, Wilmington, Del.), polypropylene,polytetrafluoroethylene (PTFE), expanded PTFE (ePTFE), polyether etherketone (PEEK), nylon, extruded collagen, polymer foam, silicone rubber,polyethylene terephthalate, ultra high molecular weight polyethylene,polycarbonate urethane, polyurethane, polyimides, stainless steel,nickel-titanium alloy (e.g., Nitinol), titanium, stainless steel,cobalt-chrome alloy (e.g., ELGILOY® from Elgin Specialty Metals, Elgin,Ill.; CONICHROME® from Carpenter Metals Corp., Wyomissing, Pa.). In someexamples, a biodegradable drug supply can comprise one or morebiodegradable polymers, such as protein, hydrogel, polyglycolic acid(PGA), polylactic acid (PLA), poly(L-lactic acid) (PLLA),poly(L-glycolic acid) (PLGA), polyglycolide, poly-L-lactide,poly-D-lactide, poly(amino acids), polydioxanone, polycaprolactone,polygluconate, polylactic acid-polyethylene oxide copolymers, modifiedcellulose, collagen, polyorthoesters, polyhydroxybutyrate,polyanhydride, polyphosphoester, poly(alpha-hydroxy acid) andcombinations thereof. In some examples, the drug supply can comprise ahydrogel polymer. Any drug supply matrix must be capable of compressioncontrolled release through the previously described port.

EXAMPLES

The following examples are provided in order to demonstrate and furtherillustrate certain preferred embodiments and aspects of the presentinvention and are not to be construed as limiting the scope thereof.

Example 1 One Embodiment, Supporting Data

Given the numerous fluid properties of artificial tears and othertopical medications and the elasticity components of the potentialmaterials to be used, sample calculations have been done to create alogical starting ground for experimentation. Below is summary of thecalculations performed for each of the 3 sample types (PTFE, SiliconRubber, Polyimide). Using a spreadsheet, the Benoulli's flow equation,as well as the elastic properties of the balloon material such asYoung's modulus and diameter of distal end, the following estimationshave been calculated to give a 7 microlitre/day flow rate and allow theballoon to function for 100 days:

PTFE: Inner Tube Diameter: 1.56×10⁻⁶ m Elastic Reservoir Volume: 7×10⁻⁴L Polyimide: Inner Tube Diameter: 8.43×10⁻⁷ m Elastic Reservoir Volume:7×10⁻⁴ L Silicone Rubber: Inner Tube Diameter: 3.37×10⁻⁶ m ElasticReservoir Volume: 7×10⁻⁴ L

These calculations were made by first assuming an inner tube diameterand starting elastic reservoir volume. The surface area of the inflatedballoon corresponding to the elastic reservoir volume was calculated andthus the radius of the balloon was known. Given the surface area of theballoon, Young's modulus was used to calculate a pressure exerted by theballoon on the fluid and thus a net pressure was calculated inside theballoon. Given this pressure, the density of the fluid, and theBernoulli's assumptions of free jet at the distal end point as well asnegligible fluid velocity at the balloon center, the unknown velocityvariable at the end of the device was calculated. The inner tubediameter was then iteratively adjusted to correspond to a 7 microlitreper day flow rate and further adjusted to match the 100 day lifecriteria. Using the design shown in FIG. 5, FIG. 6, and FIG. 7, 7microliters of fluid was consistently delivered over a period no lessthan 90 days.

Thus, specific compositions and methods of lacrimal system drug deliverydeviceError! No bookmark name given. have been disclosed. It should beapparent, however, to those skilled in the art that many moremodifications besides those already described are possible withoutdeparting from the inventive concepts herein. Moreover, in interpretingthe disclosure, all terms should be interpreted in the broadest possiblemanner consistent with the context. In particular, the terms “comprises”and “comprising” should be interpreted as referring to elements,components, or steps in a non-exclusive manner, indicating that thereferenced elements, components, or steps may be present, or utilized,or combined with other elements, components, or steps that are notexpressly referenced.

All publications mentioned herein are incorporated herein by referenceto disclose and describe the methods and/or materials in connection withwhich the publications are cited. The publications discussed herein areprovided solely for their disclosure prior to the filing date of thepresent application. Nothing herein is to be construed as an admissionthat the present invention is not entitled to antedate such publicationby virtue of prior invention. Further, the dates of publication providedmay be different from the actual publication dates, which may need to beindependently confirmed.

REFERENCES

-   1. Fleisher, D. et al. (1996) “Improved oral drug delivery:    solubility limitations overcome by the use of prodrugs,” Adv. Drug    Delivery Rev. 19(2), 115-130.-   2. Smith, C. D. et al. (1994) “A sensitive assay for taxol and other    microtubule-stabilizing agents,” Cancer Lett. 79(2), 213-219.-   3. Mooberry, S. L. et al. (1995) “Tubercidin stabilizes microtubules    against vinblastine-induced depolymerization, a taxol-like effect,”    Cancer Lett. 96(2), 261-266.-   4. Ro, A. J. et al. (2012) “Morphological and degradation studies of    sirolimus-containing poly(lactide-co-glycolide) discs,” Journal of    Biomedical Materials Research Part B: Applied Biomaterials 100B(3),    767-777.-   5. Sim, S. et al. “Composite Lacrimal Insert and Related Methods,”    United States Patent Application Publication Number 20100034870,    application Ser. No. 12/432,553, filed Apr. 29, 2009. (published    Feb. 11, 2010).-   6. Hubbell, J. A. et al. “Photopolymerizable biodegradable hydrogels    as tissue contacting materials and controlled-release carriers,”    U.S. Pat. No. 5,410,016, application Ser. No. 08/022,687, filed Mar.    1, 1993. (issued Apr. 25, 1995).-   7. Rodstrom, T. R. et al. “Punctal Plugs and Methods of Delivering    Therapeutic Agents,” United States Patent Application Publication    Number 20080181930, application Ser. No. 12/022,520, filed Jan.    30, 2008. (published Jul. 31, 2008).-   8. Borgia, M. J. et al. “Punctal Plugs for the Delivery of Active    Agents,” United States Patent Application Publication Number    20070298075, application Ser. No. 11/759,327, filed Jun. 7, 2007.    (published Dec. 27, 2007).-   9. Beeley, N. R. F. and Coldren, B. A. “Punctal Plugs for Controlled    Release of Therapeutic Agents,” United States Patent Application    Publication Number 20110251568, application Ser. No. 13/043,171,    filed Mar. 8, 2011. (published Oct. 13, 2011).-   10. Brubaker, M. J. et al. “Sustained Release Drug Delivery    Devices,” WIPO PCT Patent Publication Number WO/2002/056863,    Application PCT/US2001/048804, filed Jul. 25, 2002. (published Dec.    17, 2001).-   11. Rapacki, A. R. et al. “Lacrimal Implants and Related Methods,”    United States Patent Application Publication Number 20100274204,    application Ser. No. 12/710,855, filed Feb. 23, 2010. (published    Oct. 28, 2010).-   12. Cohan, B. E. “Opthalmic insert and method for sustained release    of medication to the eye,” European Patent EP1891942B1, Application    EP1178779A1, filed Apr. 7, 2000. (issued Mar. 3, 2010).-   13. Murube, J. et al. (2003) “Subcutaneous abdominal artificial    tears pump-reservoir for severe dry eyes,” Orbit 22(1), 29.

We claim:
 1. A lacrimal system drug delivery device, comprising: a) areservoir having a loading port and an exit port wherein said reservoirhas elastic properties, b) a first tube connected to said exit port, andc) a second tube comprising a flow limiting port connected to said firsttube.
 2. The device of claim 1, wherein said device further comprises athird tube connected to said loading port.
 3. The device of claim 2,wherein said elastic reservoir further comprises a fluid comprising acomposition with an active ingredient.
 4. The device of claim 1, whereinsaid elastic reservoir enables anatomical fixation.
 5. The device ofclaim 4, wherein said anatomical fixation is a device retention feature.6. The device of claim 1, wherein said exit port is connected to aninternal plunger.
 7. The device of claim 6, wherein said exit port isconnected to internal springs connected to said internal plunger.
 8. Thedevice of claim 7, wherein said device further comprise amicroelectromechanical systems spring pressure regulator.
 9. The deviceof claim 1, wherein said device is made of bioerodible materials. 10.The device of claim 1, wherein said device is made of microporousmaterials.
 11. The device of claim 1, wherein said device is made ofnanoporous materials.
 12. The device of claim 1, wherein said device ismade of medical grade materials.
 13. The device of claim 1, wherein saidflow limiting port comprises at least one hole.
 14. The device of claim1, wherein said flow limiting port comprises a filter.
 15. The device ofclaim 1, wherein said flow limiting port comprises at least one ePTFEmembrane.
 16. The device of claim 3, wherein the flow of said fluid outof said device is gravity dependent.
 17. The device of claim 3, whereinthe flow of said fluid out of said device is limited by a gravitydependent valve.
 18. A method of treatment, comprising: a) providing: i)a subject comprising lacrimal ducts and a lacrimal sac, ii) a lacrimalsystem drug delivery device, comprising: A) an elastic reservoircomprising a composition with at least one active ingredient, whereinsaid reservoir is capable of insertion inside said lacrimal sac, B) afirst tube with a lumen extending from said elastic reservoir through atleast one of the lacrimal ducts, and C) a second tube with a flowlimiting port connected to said first tube, wherein said second tubeterminates with said flow limiting port in a punctum in contact with thetear film of the eye, b) inserting said drug delivery device into saidlacrimal system; and c) administering said composition to said subjectusing said lacrimal system drug delivery device.
 19. The method of claim18, wherein said device further comprises an internal spring connectedto an internal plunger connected to said exit port.
 20. The method ofclaim 19, wherein said internal plunger enables the constant release ofsaid composition without relying on said elastic reservoir.
 21. Themethod of claim 19, wherein said device further comprises amicroelectromechanical systems spring pressure regulator.
 22. The methodof claim 18, wherein said device further comprises a third tubeconnected to said elastic reservoir, wherein said third tube extendsfrom said elastic reservoir into the nasolacrimal duct wherein itterminates.
 23. The method of claim 18, wherein said device furthercomprises a cut-off valve.
 24. The method of claim 18, wherein saiddevice comprises bioerodible materials.
 25. The method of claim 24,wherein said device comprises internal composition columns with saidbioerodible materials.
 26. The method of claim 25, wherein the erosionof said bioerodible materials open up inlet pores sequentially allowingalong said internal composition column which would enable for pulseddosing of said composition.
 27. The method of claim 18, wherein saidactive ingredient consists of artificial tears, glaucoma drops,anti-inflammatory agents, nonsteroidal agents, antibiotics, biologics,proteins, aptamers, nucleic acids, cytokines, plasma, sympahtomemetics,parasympathomemetics, prostaglandin analogues, beta blockers,alpha-agonists, and anti-VEGF agents.
 28. The method of claim 22,wherein said elastic reservoir may be accessed through said third tubefor the process of flushing and refilling.
 29. The method of claim 23,wherein the flow of said fluid out of said device is controlled by acut-off valve that is accessible by an operator to decrease flow atgiven times when treatment is not desired.
 30. The method of claim 18,wherein said flow limiting port regulates the flow of said compositionfrom said device.
 31. The method of claim 18, wherein said flow limitingport comprises at least one ePTFE membrane.
 32. The method of claim 18,wherein said flow limiting port comprises at least one layer of ePTFEmaterial.